This proposal seeks to apply concepts from evolutionary biology to the study of both human and non-human malaria parasites, with the broad goal of gaining analyzing their phylogenetic relationships and of characterizing the amount, origin and manner of maintenance of genetic diversity in various genes encoding human candidate immunogens. Four primary aims are to be pursued, including: (1) to establish phylogenetic relationships relating the various mammalian malaria parasites to each other and to those of other Haemosporina, emphasizing the origins and evolutionary history of P. falciparum and P. vivax; (2) using this phylogenetic tree as a base, to identify factors affecting the evolution of major candidate vaccine immunogens; 3) to compare the extent, origin and maintenance of genetic diversity among candidate immunogens from geographically diverse samples of P. falciparum and of P. vivax; and 4) to correlate intra-host parasite genetic diversity and clinical manifestations of disease in P. falciparum-infected children in western Kenya. Overall, the proposed body of work seeks to establish the origins of the malaria parasites, to provide a basis for developing a multivalent malaria vaccine and to define the distribution of genetic diversity among malaria parasites across a broad geographic area.